Parkinson's Disease (PD) is one of the most prevalent of the neurodegenerative disorders. PD results from the death of 60-70% of the dopaminergic neurons located in the substantia nigra pars compacta. The motor symptoms of the disease are characterized by bradykinesia or akinesia, rigidity, resting tremors, and gait disturbances (Fahn, Ann. N.Y. Acad. Sci. 991:1-14 (2003)). Currently, dopamine replacement therapy with levodopa is the most widely accepted treatment for PD. Chronic use of the drug, however, leads to long-term complications, such as on-off states and dyskinesia, for about 60% of the patients. Moreover, a large percentage of these patients become unresponsive to the drug, rendering such pharmacological therapy ineffective after a few years.
The most common alternative to dopamine replacement therapy is the direct electrical stimulation of deep brain areas, such as the basal ganglia and thalamus. This therapy is generically known as Deep Brain Stimulation (DBS). In patients with severe PD motor symptoms, chronic continuous high frequency electrical stimulation of motor brain regions, such as the subthalamic nucleus, globus pallidus, or thalamus, can decrease tremors, rigidity, and bradykinesia. DBS also permits the reduction of dopaminergic medication, minimizing the long-term side effects associated with pharmacotherapy.
Unfortunately, DBS requires a stereotactic, high-precision, intracranial surgical procedure, and its efficacy depends on the accuracy of targeting brain nuclei. Additionally, DBS surgery can be associated with serious complications, including intracranial hemorrhage (3.9%) and infections (1.7%). Adverse events related to the device include electrode replacement (4.4%), device dysfunction (3.0%), infection (1.9%) and migration (1.52%) (Kleiner-Fisman et al, Mov. Disord. 21, Suppl 14:5290-5304 (2006)). Thus, despite clear advantages of DBS over L-DOPA therapy, its use is typically restricted to patients in the late stages of PD that are medically stable enough to undergo surgery. That restricts considerably the total number of patients who can benefit from this rather invasive neurosurgical procedure.
The precise neural mechanism by which DBS exerts it effects remains unknown. However, some evidence suggests that its action occurs through the disruption of characteristic aberrant low frequency (<10 Hz) synchronized activity of neuronal populations of basal ganglia and/or motor cortex observed in parkinsonian states (Brown, Mov. Disord. 18:357-363 (2003); Brown et al, Exp. Neurol. 188:480-490 (2004); Costa et al, Neuron. 52:359-369 (2006); Gatev et al, Mov. Disord. 21:1566-1577 (2006)).
The present invention provides new approaches to the utilization of neurostimulation as a continuous therapy for controlling the primary motor symptoms of PD and other movement disorders (e.g. essential tremor (Benabid et al, Lancet 337:403-406 (1991))). The methods to which the invention relates are less invasive than DBS and avoid the complications associated with intracranial surgery.